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Nature. 2019 Aug;572(7768):254-259. doi: 10.1038/s41586-019-1410-1. Epub 2019 Jul 17.

Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion.

Author information

1
Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
2
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Tuebingen, Germany.
3
Department of Internal Medicine II, Hematology and Oncology, Eberhard-Karls University, Tuebingen, Germany.
4
DFG Cluster of Excellence 2180 'Image-guided and Functional Instructed Tumor Therapy' (IFIT), Eberhard-Karls University, Tuebingen, Germany.
5
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
6
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
7
Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
8
Division of Clinical Hematology, University Hospital Basel, Basel, Switzerland.
9
University Children's Hospital Basel, Basel, Switzerland.
10
Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany.
11
Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
12
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
13
Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, USA.
14
Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
15
Beckman Research Institute, Duarte, CA, USA.
16
Institute for Pathology & Medical Genetics, University Hospital Basel, Basel, Switzerland.
17
Diagnostic Hematology, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland.
18
Institute for Pathology, University of Tuebingen, Tuebingen, Germany.
19
Institute for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.
20
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
21
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Tuebingen, Germany. helmut.salih@med.uni-tuebingen.de.
22
Department of Internal Medicine II, Hematology and Oncology, Eberhard-Karls University, Tuebingen, Germany. helmut.salih@med.uni-tuebingen.de.
23
DFG Cluster of Excellence 2180 'Image-guided and Functional Instructed Tumor Therapy' (IFIT), Eberhard-Karls University, Tuebingen, Germany. helmut.salih@med.uni-tuebingen.de.

Abstract

Patients with acute myeloid leukaemia (AML) often achieve remission after therapy, but subsequently die of relapse1 that is driven by chemotherapy-resistant leukaemic stem cells (LSCs)2,3. LSCs are defined by their capacity to initiate leukaemia in immunocompromised mice4. However, this precludes analyses of their interaction with lymphocytes as components of anti-tumour immunity5, which LSCs must escape to induce cancer. Here we demonstrate that stemness and immune evasion are closely intertwined in AML. Using xenografts of human AML as well as syngeneic mouse models of leukaemia, we show that ligands of the danger detector NKG2D-a critical mediator of anti-tumour immunity by cytotoxic lymphocytes, such as NK cells6-9-are generally expressed on bulk AML cells but not on LSCs. AML cells with LSC properties can be isolated by their lack of expression of NKG2D ligands (NKG2DLs) in both CD34-expressing and non-CD34-expressing cases of AML. AML cells that express NKG2DLs are cleared by NK cells, whereas NKG2DL-negative leukaemic cells isolated from the same individual escape cell killing by NK cells. These NKG2DL-negative AML cells show an immature morphology, display molecular and functional stemness characteristics, and can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplant models. Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) represses expression of NKG2DLs. Genetic or pharmacologic inhibition of PARP1 induces NKG2DLs on the LSC surface but not on healthy or pre-leukaemic cells. Treatment with PARP1 inhibitors, followed by transfer of polyclonal NK cells, suppresses leukaemogenesis in patient-derived xenotransplant models. In summary, our data link the LSC concept to immune escape and provide a strong rationale for targeting therapy-resistant LSCs by PARP1 inhibition, which renders them amenable to control by NK cells in vivo.

PMID:
31316209
DOI:
10.1038/s41586-019-1410-1

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